Calvin Scott & Company, Inc. MARCS-CMS 606987 — August 25, 2020

WARNING LETTER

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• Delivery Method: VIA SIGNATURE CONFIRMED DELIVE
• Product: Drugs

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• Recipient: Mr. Jan-Erik Palm; President; Calvin Scott & Company, Inc.; 1104 W Bay Ave; Newport Beach, CA 92661; United States

• Issuing Office: Division of Pharmaceutical Quality Operations IV; United States

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August 25, 2020

Dear Mr. Palm:

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Calvin Scott and Company Inc., FEI 1619076, at 209 Eubank Blvd NE, Albuquerque, New Mexico, from March 9 to 12, 2020.

This warning letter summarizes significant violations of current good manufacturing practice (CGMP) regulations for finished pharmaceuticals. See Title 21 Code of Federal Regulations (CFR), parts 210 and 211 (21 CFR 210 and 211).

Because your methods, facilities, or controls for manufacturing, processing, packing, or holding do not conform to CGMP, your drug products are adulterated within the meaning of section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), 21 U.S.C. 351(a)(2)(B).

We reviewed your April 1, 2020, response in detail and acknowledge receipt of your subsequent correspondence.

During our inspection, our investigator observed specific violations including, but not limited to, the following.

1. Your firm failed to assure that the drug product bore an expiration date that was supported by appropriate stability testing (21 CFR 211.137(a)).

You repackaged some drug products into container-closure systems that were not equivalent to the manufacturer’s container-closure system. Specifically, for the drug product hydrochlorothiazide tablets, USP, 25 mg you repackaged this product from (b)(4) into heat-sealed pouches with one transparent side.

Your firm does not have stability data to support the expiration dates you assigned to this repackaged drug product. The manufacturer’s container requires that the drug product be dispensed “in tight, light-resistant container as defined in the USP.”

In your response, you stated that you have discontinued using heat-sealed pouches that are clear on one side and will test your replacement container-closure systems to demonstrate that they meet manufacturer recommendations for light protection.

We further acknowledge your decision to recall all drug products that you repackaged into heat-sealed pouches with one transparent side instead of a light-resistant container closure system.

Your response is inadequate because your container-closure system assessment did not address other vulnerabilities of the drug products beyond light sensitivity. This includes but is not limited to moisture vapor transmission, oxygen transmission, and compatibility of the container-closure system with the drug product. In addition, you did not provide a stability protocol and data to evaluate if the expiration dates assigned to your repackaged drug products are appropriate.

In response to this letter, provide:

• A comprehensive assessment of your stability program and CAPA plan to ensure that the expiration dates assigned to your repackaged products are scientifically justified. This plan should also include an assessment of the stability of products currently on the U.S. market within expiry. Your remediation program should include, but not be limited to:
  o Stability indicating methods and protocol for repackaged products
  o Stability studies for products in their repackaged container-closure system
  o An ongoing program in which representative batches of products are added to the program to determine if shelf-life claims remain valid
  o Detailed definition of the specific attributes to be tested at each station (timepoint)

• All procedures that describe these and other elements of your remediated stability program.

2. Your firm failed to establish and follow adequate written procedures for cleaning and maintenance of equipment (21 CFR 211.67(b)).

You repackaged various drug products that shared product contact surfaces on non-dedicated repackaging lines. You lacked cleaning validation studies to demonstrate that your cleaning procedures for this non-dedicated equipment are adequate to prevent cross-contamination between the drug products repackaged at your facility.

In your response, You acknowledged that you have not performed cleaning validation and that you have ceased distribution of repackaged drug products until products have been tested for identity, strength, quality, and purity. You stated that you initiated a cross-contamination testing study in which you will repack drug products identified as depositing the most residue onto the repackaging line. Samples from these repackaged drug products will then be sent to a third-party testing laboratory for carryover cross-contamination analyses.

Your response is inadequate because you did not perform an appropriate study to demonstrate that your cleaning program is effective.

In response to this letter, provide:

• A comprehensive assessment and Corrective and Preventive Action (CAPA) plan of your cleaning program that includes appropriate remediations to your cleaning processes and practices, and timelines for completion. Provide a detailed summary of vulnerabilities in your process for lifecycle management of equipment cleaning. Describe improvements to your cleaning program, including enhancements to cleaning effectiveness; improved ongoing verification of proper cleaning execution for all products and equipment; and all other needed remediations.

• Appropriate improvements to your cleaning validation program, with special emphasis on incorporating conditions identified as worst case in your drug manufacturing operation. This should include but not be limited to identification and evaluation of all worst-case:

  o products with higher toxicities
  o products with higher potencies
  o products of lower solubility in your cleaning solvents
  o products with characteristics that make them difficult to clean
  o swabbing locations for areas that are most difficult to clean
  o maximum hold times before cleaning

In addition, describe the steps that must be taken in your change management system before introduction of new manufacturing equipment or a new product.

• A summary of updated SOPs that ensure an appropriate program is in place to verify and validate cleaning procedures for products, processes, and equipment.
• A comprehensive, independent written evaluation of packaging and labeling operations, with emphasis on failure modes, capability, and design sufficiency. Provide an analysis including but not limited to the following factors:
  o All human interactions with equipment before, during, and after (e.g., clearance) operations to identify all points with potential for human error
  o Equipment design and suitability for intended use
  o Capability of all process steps
  o Retrospective review of batches (i.e., defect types and frequencies; deviations; complaints; related investigations)
  o Analysis of equipment maintenance and repair history
  o Sufficiency of all detection systems and related analytics
  o Facility layout and personnel/material flow
  o A comprehensive final inspection of packaging integrity and labeling accuracy, and full recording of the number and type of defects

3. Your firm failed to establish a quality control unit with the responsibility and authority to approve or reject all components, drug product containers, closures, in-process materials, packaging materials, labeling, and drug products (21 CFR 211.22(a)).

You failed to establish a quality unit (QU) to carry out quality control unit responsibilities, including but not limited to final review and approval functions for drug products you distributed. Multiple personnel in your manufacturing operation had the authority to perform quality control unit responsibilities, including release of drug products for distribution. However, there is no assurance that you have appropriate separation of approval or rejection authority for final drug product release from personnel performing repackaging operations. Final drug product release should be performed by a QU, which should be independent of production.

In your response, you noted that you lack a QU, and have engaged a consultant to assist you with implementing your plans for remediation. You added that you have temporarily retained an experienced individual to carry out responsibilities as Quality Assurance Director, until this position is permanently filled. You also stated you are in the process of hiring a Quality Control (QC) Technician to carry out QC related functions.

Your response is inadequate because you failed to assure that your QU functions independently, and with appropriate responsibility and authority. You must provide your QU with the appropriate responsibility, authority, and enough resources to carry out its responsibilities and consistently ensure drug quality.

See FDA’s guidance document Quality Systems Approach to Pharmaceutical CGMP Regulations for help implementing quality systems and risk management approaches to meet the requirements of CGMP regulations 21 CFR, parts 210 and 211 at https://www.fda.gov/media/71023/download

In response to this letter, provide:

• A comprehensive independent assessment and remediation plan to ensure your QU is given the authority and resources to effectively function. The assessment should also include, but not be limited to:

  o A description of how you will ensure that your QU functions independently of other units
  o A determination of whether procedures used by your firm are robust and appropriate
  o Provisions for QU oversight throughout your operations to evaluate adherence to appropriate practices
  o A complete and final review of each batch and its related information before the QU disposition decision
  o Oversight and approval of investigations and discharge of all other QU duties to ensure identity, strength, quality, and purity of all products

• A retrospective evaluation of your products that remain on the U.S. market. Address any product quality risks or issues that occurred due to deficient practices or deviations. Include a full CAPA plan and provide notifications to customers as needed (and recalls, as appropriate).

CGMP Consultant Recommended

Based upon the nature of the violations we identified at your firm, we strongly recommend engaging a consultant, qualified as set forth in 21 CFR 211.34, to assist your firm in meeting CGMP requirements.

Your use of a consultant does not relieve your firm’s obligation to comply with CGMP. Your firm’s executive management remains responsible for resolving all deficiencies and systemic flaws to ensure ongoing CGMP compliance.

Conclusion

The violations cited in this letter are not intended to be an all-inclusive list of violations that exist at your facility. You are responsible for investigating and determining the causes of these violations and for preventing their recurrence or the occurrence of other violations.

If you are considering an action that is likely to lead to a disruption in the supply of drugs produced at your facility, FDA requests that you contact CDER’s Drug Shortages Staff immediately, at drugshortages@fda.hhs.gov, so that FDA can work with you on the most effective way to bring your operations into compliance with the law. Contacting the Drug Shortages Staff also allows you to meet any obligations you may have to report discontinuances or interruptions in your drug manufacture under 21 U.S.C. 356C(b). This also allows FDA to consider, as soon as possible, what actions, if any, may be needed to avoid shortages and protect the health of patients who depend on your products.

Correct the violations cited in this letter promptly. Failure to promptly correct these violations may result in legal action without further notice including, without limitation, seizure and injunction. Unresolved violations in this warning letter may also prevent other Federal agencies from awarding contracts.

FDA may also withhold approval of requests for export certificates and approval of pending new drug applications or supplements listing your facility as a supplier or manufacturer until the above violations are corrected. We may re-inspect to verify that you have completed your corrective actions.

After you receive this letter, respond to this office in writing within 15 working days. Specify what you have done since our inspection to correct your violations and to prevent their recurrence. If you cannot complete corrective actions within 15 working days, state your reasons for delay and your schedule for completion.

Please send your electronic reply to ORAPharm4_responses@fda.hhs.gov or mail your reply to:

CDR Steven E. Porter, Jr.
Director, Division of Pharmaceutical Quality Operations IV
19701 Fairchild Road
Irvine, CA 92612-2506

Please identify your response with unique identifier 606987.

If you have questions regarding any issues in this letter, please contact Dr. Matthew R. Dionne, Compliance Officer via email at Matthew.Dionne@fda.hhs.gov or by phone at (303)-236-3064.

Sincerely,
/S/

CAPT Katherine E. Jacobitz
Acting Director, Division of Pharmaceutical Quality Operations IV

CC:

Ms. Rachel C. Martin, Director of Operations
Calvin Scott and Company, Inc.
209 Eubank Blvd NE
Albuquerque, NM 87123